Project Summary: The Federal Pain Research Strategy highlights the need for investigation of biological mechanisms that underlie the treatment effects of non-pharmacological interventions in pediatric chronic pain patients. Understanding biological mechanisms can advance the use of effective treatments such as cognitive behavioral therapy (CBT) by providing patients and families with a stronger rationale for treatment, thereby decreasing stigma and increasing confidence in and commitment to the care plan. In addition, mechanstic insights foster patients' ability to effectively participate in shared decision-making and self-management, may provide for more individualized and precise care, and will increase uptake by health care providers, patients, and payors. Neuroimaging and quantitative sensory testing (QST) are techniques that can provide insight into the biological basis for pain treatment effects. This project will study migraine, which affects > 6 million youth in the U.S. Cochrane reviews show that psychological therapies for pediatric headache result in better outcomes than control conditions (56% improved vs. 22% in 714 participants), and our CBT+Amitriptyline Study found that 66% of youth with chronic migraine had a ? 50% reduction in headache days compared to 36% in an education control+Amitriptyline (AMI) group. Despite this evidence base, the neural mechanisms supporting the efficacy of CBT for pain remain poorly understood. The lack of mechanistic understanding is a barrier to treatment utilization, particularly given the time, effort, and expense for pediatric migraine patients to receive CBT vs. conventional pharmacological therapy (which in a national trial reduced headache days similar to placebo pill: AMI 52% of participants improved; Placebo 61%). Pilot data from our group demonstrate that: CBT induces changes in brain connectivity/activation, and QST at baseline predicts reduced migraines at 8 weeks. These findings show proof of concept specific to pediatric migraine patients and refined the design of this project, which will recruit 240 youth ages 10 to 17 with migraine to undergo functional MRI and QST before and after 8 weeks of either CBT, placebo, or AMI to address these aims: Aim 1: Does CBT engage brain mechanisms which are distinct from those engaged by pill-based therapy (placebo & AMI)? Aim 2: Are poorer baseline pain modulatory mechanisms measured by QST predictive of greater headache day reduction from CBT vs. pill-based therapy? Exploratory Aims: a. Assess whether brain changes at 8 weeks in those who receive CBT play a mediational role when outcomes are assessed at a 3 month follow-up; b. Test if the findings from Aims 1 and 2 are supported when other pain contextual variables (anxiety, depression, sleep) are included in the statistical models; c. Compare neuroimaging between placebo and AMI; d. All analyses will include age, sex, pubertal status, and brain structural connectivity in the statistical models to assess developmental variables. Pediatric medical and behavioral clinicians can use mechanistic insights from translational investigations such as this project to enhance the care they provide to youth with migraine.